Background: Diabetic heart dysfunction is a common complication of diabetes. Cell death is a core event that leads to diabetic heart dysfunction. However, the time sequence of cell death pathways and the precise time to intervene of particular cell death type remain largely unknown in the diabetic heart. This study aims to identify the particular cell death type that is responsible for diabetic heart dysfunction and to propose a promising therapeutic strategy by intervening in the cell death pathway. Methods: Type 2 diabetes models were established using db/db leptin receptor–deficient mice and high-fat diet/streptozotocin–induced mice. The type 1 diabetes model was established in streptozotocin-induced mice. Apoptosis and programmed cell necrosis (necroptosis) were detected in diabetic mouse hearts at different ages. G protein–coupled receptor–targeted drug library was searched to identify potential receptors regulating the key cell death pathway. Pharmacological and genetic approaches that modulate the expression of targets were used. Stable cell lines and a homemade phosphorylation antibody were prepared to conduct mechanistic studies. Results: Necroptosis was activated after apoptosis at later stages of diabetes and was functionally responsible for cardiac dysfunction. Cannabinoid receptor 2 (CB2R) was a key regulator of necroptosis. Mechanically, during normal glucose levels, CB2R inhibited S6 kinase–mediated phosphorylation of BACH2 at serine 520, thereby leading to BACH2 translocation to the nucleus, where BACH2 transcriptionally repressed the necroptosis genes Rip1 , Rip3 , and Mlkl . Under hyperglycemic conditions, high glucose induced CB2R internalization in a β-arrestin 2–dependent manner; thereafter, MLKL (mixed lineage kinase domain-like), but not receptor-interacting protein kinase 1 or 3, phosphorylated CB2R at serine 352 and promoted CB2R degradation by ubiquitin modification. Cardiac re-expression of CB2R rescued diabetes-induced cardiomyocyte necroptosis and heart dysfunction, whereas cardiac knockout of Bach2 diminished CB2R-mediated beneficial effects. In human diabetic hearts, both CB2R and BACH2 were negatively associated with diabetes-induced myocardial injuries. Conclusions: CB2R transcriptionally repressed necroptosis through interaction with BACH2; in turn, MLKL formed a negative feedback to phosphorylate CB2R. Our study provides the integrative view of a novel molecular mechanism loop for regulation of necroptosis centered by CB2R, which represents a promising alternative strategy for controlling diabetic heart dysfunction.

Short-form video sharing platforms (SVSPs) have seen a significant surge in older adult content creators in recent years. This emerging trend adds evidence to challenge the conventional perception of older adults as later technology adopters and passive online recipients. To investigate the reason behind the trend, we conducted semi-structured interviews with 13 older adult content creators on two of the most popular SVSPs in China, DouYin and KuaiShou. We found that our participants were initially attracted to SVSPs because of perceived ease of participation and the enjoyment they found. However, what kept them engaged was the attention and support they received there. SVSPs offered a low-barrier and equitable platform through their near-automatic use and relatively equal opportunities for recommendations, allowing everyone to reach audiences. Motivated by their passion for performance and the viewers' support, our participants actively acquired new skills for better performance and became more deeply involved on the platforms. Based on the findings, we reflect on how SVSPs' technical affordances support older adults in the transition from lurkers to contributors. We advocate for participation equity and supportive environments to promote more inclusive social media platforms.

HCI and CSCW research has witnessed increasing efforts to address diversity and inclusion in research and design practice, as evidenced by the growing body of research with populations deemed as vulnerable, marginalized, or underserved. However, this work has been largely limited to a population-specific approach, i.e., identifying certain populations as vulnerable and gathering their individual experiences. Drawing primarily from human-centered security and privacy research, we identify three key challenges faced by this population-specific approach: (1) It is limited in addressing user diversity within the target population; (2) It may fail to capture the complex social reality of vulnerability; and (3) It runs the risk of perpetuating othering and stereotypes. To address these limitations, we propose a socio-ecological perspective on vulnerability adapted from the Ecological System Theory (EST). We argue that a socio-ecological perspective of vulnerability can guide researchers to look beyond static and stigmatizing definitions of vulnerability --- instead, focus on the situations, relations, and structures that lead to vulnerability, eventually enabling transferable knowledge of vulnerability across populations. We demonstrate how the socio-ecological lens maps onto existing work and generates new insights in the case of older adults' security and privacy, as well as its potential for being applied to other contexts such as reproductive privacy and responsible artificial intelligence. We end by providing concrete recommendations on how HCI and CSCW research can better operationalize vulnerability in scholarship and design practice.